The new epigenetic driver role of PPARα and mitochondria in metabolic dysfunction associated liver disease (MASLD), paving the way towards new therapeutics and diagnostic biomarkers
Metabolic dysfunction associated fatty liver disease (MASLD) is a global health burden. It consists of a spectrum of liver disorders ranging from steatosis, characterized by lipid accumulation in the liver, inducing inflammation and thereby progression into metabolic dysfunction associated steatohepatitis (MASH). MASH predisposes patients for further cirrhosis and hepatocarcinoma. Unfortunately, there is still no FDA-approved treatment due to the lack of biomarkers to correctly stratify patients and the multifactorial nature of the disease. Therefore changes in lifestyle including diet and exercise remain the current treatment strategy. However this is difficult to maintain, leading to a lot of relapsing patients. Thus, there is an urgent need for a full characterization of the molecular targets that have a key role in the progression of the disease. The nuclear receptor PPARα and mitochondria have a key role in lipid metabolism and are also closely related to inflammation. Moreover, recent research, especially cancer research, has shown that mitochondrial DNA (mtDNA) methylation can be used as a biomarker and interactions of PPARα with epigenetic enzymes can regulate lipid metabolism in liver and colon, which makes them interesting targets. PPARα is epigenetically downregulated in MASH patients, but previously tested agonists could not ameliorate the disease. Interestingly, we show that the loss of PPARα function by diet induces similar epigenetic and transcriptional changes towards a MASLD gene signature, as a genetic knock out. Moreover, in both mice models, the loss of this one PPARα hub induced a shockwave of changes in the transcriptome of several epigenetic enzymes, resulting in the epigenetic reprogramming of the lipid and bile acid metabolism towards ferroptotic and pyroptotic lipotoxicity that is closely related with fibrosis. This suggests an important indirect epigenetic protective function of PPARα towards its target genes, to maintain general lipid homeostasis and prevent progression of MASLD. Therefore combination therapies of PPARα agonists with epigenetic compounds should be explored. Due to the constant accumulation of lipids in the liver, MASH patients show an overactivation of the mitochondrial metabolism. However the exact molecular mechanisms leading to this overactivation and eventually shutdown are still largely unknown. We have shown that MASLD is associated with small changes of mtDNA methylation. Moreover, an artificial increase of 20% mitochondrial CpG or GpC methylation induced mitochondrial dysfunction and dysregulation of the bile acid metabolism by mito-nuclear communication as seen in MASLD progression. Therefore also mitochondrial methylation shows new opportunities for both MASLD biomarker and therapeutic research.
Antwerp : University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Biomedical Sciences , 2024
204 p.
Supervisor: Vanden Berghe, Wim [Supervisor]
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Creation 11.01.2024
Last edited 31.01.2024
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